Li-ion batteries (LIB) are increasingly used worldwide. They are made of low solubility micrometric particles, implying a potential for inhalation toxicity in occupational settings and possibly for consumers. LiCoO2 (LCO), one of the most used cathode material, induces inflammatory and fibrotic lung responses in mice. LCO also stabilizes hypoxia-inducible factor (HIF) -1α, a factor implicated in inflammation, fibrosis and carcinogenicity. Here, we investigated the role of cobalt, nickel and HIF-1α as determinants of toxicity, and evaluated their predictive value for the lung toxicity of LIB particles in in vitro assays. By testing a set of 5 selected LIB particles (LCO, LiNiMnCoO2, LiNiCoAlO2) with different cobalt and nickel contents, we found a positive correlation between their in vivo lung inflammatory activity, and (i) Co and Ni particle content and their bioaccessibility and (ii) the stabilization of HIF-1α in the lung. Inhibition of HIF-1α with chetomin or PX-478 blunted the lung inflammatory response to LCO in mice. In IL-1β deficient mice, HIF-1α was the upstream signal of the inflammatory lung response to LCO. In vitro, the level of HIF-1α stabilization induced by LIB particles in BEAS-2B cells correlated with the intensity of lung inflammation induced by the same particles in vivo. We conclude that HIF-1α, stabilized in lung cells by released Co and Ni ions, is a mechanism-based biomarker of lung inflammatory responses induced by LIB particles containing Co/Ni. Documenting the Co/Ni content of LIB particles, their bioaccessibility and their capacity to stabilize HIF-1α in vitro can be used to predict the lung inflammatory potential of LIB particles.

中文翻译：

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HIF-1α是锂离子电池颗粒肺部炎症潜能的关键介质

锂离子电池（LIB）在世界范围内得到越来越多的使用。它们由低溶解度的微米级颗粒制成，这意味着在职业环境中以及可能对消费者具有吸入毒性的潜力。LiCoO2（LCO）是最常用的阴极材料之一，可在小鼠中诱发炎症和纤维化的肺部反应。LCO还可以稳定低氧诱导因子（HIF）-1α，该因子与炎症，纤维化和致癌性有关。在这里，我们调查了钴，镍和HIF-1α作为毒性决定因素的作用，并评估了它们在体外测定中对LIB颗粒对肺部毒性的预测价值。通过测试一组5种选定的具有不同钴和镍含量的LIB颗粒（LCO，LiNiMnCoO2，LiNiCoAlO2），我们发现它们的体内肺部炎症活性呈正相关，（i）Co和Ni颗粒含量及其生物可及性（ii）肺中HIF-1α的稳定化。HIF-1α被化学趋化因子或PX-478抑制会减弱小鼠对LCO的肺部炎症反应。在IL-1β缺陷型小鼠中，HIF-1α是肺对LCO的炎症反应的上游信号。在体外，LIS颗粒在BEAS-2B细胞中诱导的HIF-1α稳定水平与体内相同颗粒诱导的肺部炎症强度相关。我们得出的结论是，通过释放的Co和Ni离子在肺细胞中稳定的HIF-1α是由含Co / Ni的LIB颗粒诱导的肺炎症反应的基于机制的生物标志物。记录LIB颗粒的Co / Ni含量，